Solid dosage forms are preferential in pharmaceutical industry, especially tablets. To attain tablets of a sufficient quality pharmaceutical excipients which do not possess pharmacologic activity are used and are added to active pharmaceutical ingredient, in particular to enhance tableting properties that are essential for production of tablets.
Important group of pharmaceutical excipients are fillers, comprising different sugars, wherein lactose is the most extensively used in a pharmaceutical industry. In pharmaceutical processing is vital that said fillers demonstrate suitable properties, in particular good flowability and compressibility, especially with regard to tablets (Bolhuis K G, Armstrong A N. Excipients for direct compaction—un update. Pharmaceutical Development Technology 2006; 11: 111-124). Commercially accessible types of lactose for direct compression are prepared by different methods, therefore they possess different physicochemical properties with an intention to improve process difficulties with regard to poor flowability and/or compressibility. (Rowe R C, Sheskey P J, Quinn M R (Eds). Lactose, monohydrate in Handbook of Pharmaceutical Excipients 6th Ed., Pharmaceutical Press, 2009). Lactose is frequently produced with crystallization in the first stage, followed by milling and/or sieving in the second, respectively. The outcomes of the milling process are often particles with sharp edges, irregular form and small size that can have poor tableting properties, therefore are commonly subject of improvement. This is often achieved by procedures comprising: granulation, spray drying, physical modification of particles (dehydration, partial pregelatinization, etc.), co-processing, etc. (Bolhuis G K, Waard H. Compaction properties of directly compressible materials in Celik M (Ed). Pharmaceutical Powder Compaction Technology 2nd Ed., Informa Healthcare, 2011; Gohel M C. A review of co-processed directly compressible excipients. Journal of Pharmacological and Pharmaceutical Sciences 2005; 8: 76-93). Additional stages of manufacturing of lactose particles after crystallization are time consuming and less economical, therefore there is a substantial need for a plain, convenient and more economical process for a production of directly compressible lactose particles. Spherical crystallization, and more particularly, spherical agglomeration is considered as an adequate alternative technique to aforementioned methods.
Spherical agglomeration is a complex process, wherein crystallization of primary particles and agglomeration of said primary particles occur concurrently leading to formation of spherical agglomerates. Spherical agglomeration is only possible within maintained narrow crystallization conditions, therefore the parameters which lead to suitable conditions are difficult to discover. For effective spherical agglomeration process a plurality of, but not limited to, parameters are essential, such as composition of solvents, viscosity of a crystallization system, supersaturation of a solute solution, temperature of the crystallization system and stirring parameters that establish adequate hydrodynamic conditions. An appropriately guided process results in spherical agglomerates with adequate flow properties for tableting, high intrapartical porosity and brittleness that demonstrate great compressibility (Kovačič B, Vrečer F, Planinšek O. Spherical crystallization of drugs. Acta Pharmaceutica 2012; 62: 1-14).
The object of the present invention is to provide particles of spherically agglomerated lactose for direct compression with good flowability and compressibility produced in uniform process of spherical agglomeration without additional process stages (e.g. granulation, spray drying, etc.) required for improving flowabiltiy and compressibility.
Characteristics of particles are critical for adequate flow and compression properties of a tableting mixture in production of solid dosage forms like tablets. Flowability of a tableting mixture depends on particle size, its shape and morphology. Particles with smooth and round morphology with particle size larger than 100 μm are desired. Porosity of particles affects compression properties. The strength of tablets depends on number and potency of intraparticle and interparticle contact points that are formed during the production of dosage form, thus particles with large specific surface area and highly brittle particles are desired. Higher tablet strength prevents or minimizes very common tablet defects such as lamination and capping. Additionally, mechanical properties of tablets for handling and packaging are improved.
The simplest and most economical way of producing tablets is direct compression as it consists of two stages—blending of final tableting mixture and compression of said mixture into a tablet. Initial particles of which a tableting mixture is made of have often poor flowability and compressibility, therefore direct compression is not feasible. Hence, appropriate treatment of particles with granulation is necessary to obtain particles with good flowability and compressibility. Granulation is undesirable because specific equipment is necessary and many process stages are required to obtain tablets in comparison to direct compression.
Significant problem of a direct compression process is an occurrence of segregation or stratification of tableting mixture which has a significant influence on uniformity of content in a tablet and stability of the process itself. Segregation is commonly encountered during blending of tableting mixture, transport of tableting mixture, transfer of said mixture from blender to hopper and during tableting process because of elevated vibrations of tablet press, especially during higher tableting speeds. Segregation is mostly a consequence of difference in particle size, shape, density and adhesion forces among particles of different components in a tableting mixture. It can be limited by transformation of particles into granules but granulation is undesirable because specific equipment is necessary and many process stages are required to obtain tablets in comparison to direct compression. Segregation can be reduced or prevented by employing adequate excipient, therefore there is a substantial need for an excipient, with particles having porous structure and demonstrate suitable morphologic properties, like increased particle outer contact surface that prevents segregation.